It is essential for survival that a wound stops bleeding, i.e. that the body possesses an adequate mechanism for hemostasis. The process of blood clotting can be activated in the case of injuries or inflammations by either extrinsic or intrinsic factors, e.g. tissue factor (TF) or Hagemann factor (F XII), respectively. Both activation channels are continued in a common branch of the cascade resulting in thrombin formation. The thrombin itself finally initiates the formation of fibrin fibers, which represent the protein backbone of blood clots.
Various methods have been introduced to assess the potential of blood to form an adequate clot and to determine the blood clots stability. One group of tests is summarized by the term “viscoelastic methods”. The common feature of these methods is that the blood clot firmness (or other parameters dependent on it) is continuously determined, from the formation of the first fibrin fibers, till the dissolution of the blood clot by fibrinolysis. Blood clot firmness is a functional parameter, which is important for hemostasis in vivo, as a clot must resist blood pressure and shear stress at the site of vascular injury. Clot firmness results from multiple interlinked processes: coagulation activation, thrombin formation, fibrin formation and polymerisation, platelet activation and fibrin-platelet interaction and can be compromised by fibrinolysis. Thus, by the use of the viscoelastic monitoring all these mechanisms of the coagulation system can be assessed.
The publications and other materials referred to herein to illustrate the invention and, in particular, to provide additional details respecting the practice are incorporated herein by reference.
The first viscoelastic method was called “thrombelastography” (Hartert H: Blutgerinnungsstudien mit der Thrombelastographie, einem neuen Untersuchungsverfahren. Klin Wochenschrift 26:577-583, 1948). In the thromboelastography, the sample is placed in a cup that is periodically rotated to the left and right by about 5°. A pin is freely suspended by a torsion wire. When a clot is formed it starts to transfer the movement of the cup to the pin against the reverse momentum of the torsion wire. The movement of the pin is continuously recorded and plotted against time.
The fibrin backbone creates a mechanical, elastic linkage between the two surfaces of the blood-containing cup and a pin plunged therein. A proceeding coagulation process induced by adding one or more activating factor(s) can thus be observed. In this way, various deficiencies of a patient's hemostatic status can be revealed and used for proper medical intervention.
Modifications of the original thromboelastography technique (also called thromboelastometry) have been described by Cavallari et al. (U.S. Pat. No. 4,193,293), by Do et al. (U.S. Pat. No. 4,148,216), by Cohen (U.S. Pat. No. 6,537,819), by Hartert et al. (U.S. Pat. No. 3,714,815) and by Calatzis et al. (U.S. Pat. No. 5,777,215).
A common feature of all the methods used for coagulation diagnosis is that the blood clot is placed between two cylindrical bodies and the ability of the blood clot to couple those two bodies is determined. However, the measurement can only be evaluated as long as the fibrin network is sufficiently bound to the surfaces of these two bodies, i.e. of cup and pin. If the fibers tear off even partly, the disturbed measurement becomes hard to interpret because of interference between this effect and the pathologic pattern of hyperfibrinolysis. Unfortunately, such tear-offs of the fibrin network can occur in the case of increased thrombocyte concentrations as observable for example in the blood of hematologic patients (thrombocytosis). In these patients the strength of the blood clot is enhanced and this can lead to too strong forces on the plastic surface, which can tear the clot off the material. For that reason, an enhancement of the blood-clot adhesion strength would improve the therapeutic security considerably.
The original cup and pin material used for thromboelastometry during the forties until the seventies was stainless steel. These cups and pins were cleaned between measurements and reused.
When thromboelastometry was developed most devices used in the medical laboratory were reused and were usually made of steel, other metals, glass or other durable materials. During the sixties and seventies most of these devices have been exchanged by disposable items made of plastic. These plastic parts are usually economically produced by injection moulding or equivalent techniques.
Disposable cups and pins for the use in thromboelastometry have been described in U.S. Pat. No. 4,148,216 by Do et al and in U.S. Pat. No. 5,223,227 by Zuckerman. In the U.S. Pat. No. 5,223,227 a production process for the cup and pin material is disclosed, which involves a roughening process of the moulds used for the injection moulding of the cups and pins. Roughening of the mould is the common strategy for enhancing the surface roughness of plastic parts produced by injection moulding. In the U.S. Pat. No. 5,223,227 mechanically roughening of the mould by sand-blasting is described.
The approach of roughening the mould to roughen the surface of the cup and pin to thereby enhance the adhesion of blood on the surface of the cup and the pin has several disadvantages:
The blood-plastic interaction takes place especially in a microscopic range of the single plastic and of the fibrin molecules. In contrast, the roughness produced by the injection moulding process is in a much larger range. Because of this the plastic surfaces produced by injection moulding provide only a limited adhesion of the blood clot. This may be sufficient for the analysis of normal blood, but may be inadequate when factors are present in the blood which compete with the adhesion of fibrin onto the plastic surfaces.
To obtain a reproducible adhesion of blood on a surface it is important to have a reproducible surface roughness.
However, the surface roughness of the injection mould changes during long-term use of the mould and also varies when a new mould has to be produced, or when several cavities are used for the production of the same part (in multi-cavity injection moulding tools).
The process for reaching an identical surface roughness on an injection moulding tool compared to previously applied tools can be very expensive and time-consuming. Several surface modifications may need to be performed, sample parts have to be produced and evaluated.
In addition, the surface properties produced by injection moulding vary depending on several injection moulding parameters (pressure, temperature) as well as by the batch of the plastic material applied.
The need for improved blood-clot anchoring at artificial surfaces also exists for implants or special artery sealings. In both cases the surface properties must allow a sufficient adhesion of coagulated blood. In the case of implants the blood clot serves as a scaffold for tissue regeneration. Although most polymeric surfaces show in general a good ability to bind blood-inherent coagulation components like thrombocytes and fibrin, the maximum tearing force is not adequate in the case of higher blood pressures or vascular motions. In view of this, improvements of the blood anchoring ability at artificial surfaces enable the use of highly sufficient vascular sealings.
In conclusion a method to improve the adhesion strength of blood clots onto plastic surfaces for diagnostic as well as for biomedical uses is highly desirable.
In the last decade, a rather overwhelming number of plasma applications to enhance the biocompatibility of medical devices in blood contact was disclosed (e.g. U.S. Pat. No. 6,159,531; U.S. Pat. No. 5,591,140; U.S. Pat. No. 5,262,451). These attempts were made to reduce the common blood affinity of artificial surfaces, thus preventing disadvantageous blood clotting and/or tissue deposition. The reported applications contain surgical equipments and in-vivo implants as well as disposables for blood storage or diagnostic purposes.
From U.S. Pat. No. 5,344,611 it is known to treat the surface of, e.g. polystyrene parts with plasma, to further accelerate the clotting activation of blood in contact to surfaces made from such polymers.
There remains a need for a device to the surface of which a blood clot adheres with high adhesion strength. There is also a need for a method for preparing a surface such that the adhesion of a blood clot or to a clot of blood components to the surface is enhanced. In addition, there is a need for a device for more reliable coagulation analysis.
The present invention is directed to a method of treating the surface of a device which is to be coupled to a clot of blood or to a clot of blood components, a device which is to be coupled to a clot of blood or to a clot of blood components and a device for coagulation analysis.
The method of treating the surface is especially advantageous in that the blood adhesion strength of a clot of blood or blood components on a surface is increased compared with an untreated surface.
The device for coagulation diagnosis has, among others, the advantage over other devices that coagulation properties of blood or blood components can also be measured reliably in case of abnormal blood properties which is of high value in such a device.